The overall objectives of the research proposed for the five year period of the award are directed towards clarification of the neural substrates underlying opiate drug-related reinforcement and investigation of the role of endogenous neurotransmitters in these circuits. These studies will focus on structures within the rat limbic system, as well as their interaction with the nucleus accumbens, in an attempt to establish a more cohesive model for the processing and integration of stimuli related to drug motivated behaviors. Extracellular recording of field responses (evoked by either anti- or orthodromic stimulation of the nucleus accumbens) and spontaneous or driven unit firing from the medial prefrontal cortex, basolateral amygdala and the nucleus accumbens will be investigated in both anesthetized and freely-moving rats. The specific objectives of these studies will be (i) to electrophysiologically characterize medial prefrontal cortical neurons and to determine the effect of both systemically (I.V. or I.P.) or locally applied (iontophoresis) opiates on these cells, (2) to evaluate the neurophysiology and opiate neuropharmacology of the basolateral amygdaloid nucleus in a similar manner, (3) to determine the relative importance of input from these two limbic structures on the electrophysiologic activity of the nucleus accumbens "core" and "shell" sites (via electrical or pharmacological stimulation of these areas), (4) to evaluate the potential role of endogenous dopamine, GABA, glutamate and acetylcholine in the acute effects of opiates on the medial prefrontal cortex and basolateral nucleus of the amygdala. This series of experiments will involve the iontophoretic application of these agents (and their specific receptor agonists and antagonists) during systemic application of heroin, and (5) to define the function and potential interrelation of neurons in the media prefrontal cortex and the basolateral amygdala in unanesthetized, freely- moving rats involved in a heroin self-administration protocol. The outlined studies will establish an integrated research and training program delineating new aspects of drug abuse-related brain mechanisms, and potentially assisting in the development of treatment strategies. In addition, this project should provide an excellent opportunity for the clinician-researcher to gain scientific expertise in the complex and pertinent area of substance abuse.